EVEROLIMUS FAILED IN HCC

Everolimus (Afinitor) does not improve overall survival in patients with advanced hepatocellular carcinoma (HCC) whose disease had progressed on treatment with sorafenib (Nexavar), researchers report.

The disappointing result — from the first Everolimus for Liver Cancer Evaluation (EVOLVE-1) randomized clinical trial — represents the sixth failed phase 3 trial in liver cancer over the past 7 years, said Andrew X. Zhu, MD, PhD, from the Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston."Hepatocellular carcinoma is a huge challenge to treat. Patients with advanced HCC have a median overall survival of less than 1 year, largely because of the absence of effective therapies. It's really humbling," Dr. Zhu told Medscape Medical News.

"Since the initial sorafenib approval in 2007 by the FDA, we have made tremendous efforts to find additional target drugs for this disease," he explained. "The negative result from this study shows 3 things: that we have not selected the right drug to be tested in the right populations, that we have not designed the right trial to answer the question, and that we need to reconsider the direction about how to move the field forward."

The negative findings were published in the July 2 issue of JAMA.

There are no effective systemic therapies for the treatment of advanced HCC, aside from sorafenib. But its benefits are mostly transient and modest, and the cancer eventually progresses, the researchers note.

In preclinical models, everolimus prevented tumor progression and improved survival. The aim of EVOLVE-1 was to determine the efficacy and safety of everolimus 7.5 mg per day in patients with advanced HCC who were refractory to or intolerant of sorafenib.

The study, conducted in 17 countries from May 2010 to March 2012, involved adults with advanced HCC whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Of the 546 participants, 362 were randomized to receive everolimus and 184 were randomized to receive placebo.

Both groups also received best supportive care. Treatment continued until disease progression or intolerable toxicity.

There was no significant difference in median overall survival between the everolimus and placebo groups (7.6 vs 7.3 months). There were 303 deaths in the everolimus group and 151 in the placebo group (83.7% vs 82.1%; hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.86 - 1.27; P = .68).

Median time to progression with everolimus was 3.0 months and with placebo 2.6 months (HR, 0.93; 95% CI, 0.75 - 1.15).

The disease control rate — the percentage of patients with a best overall response (complete or partial) or stable disease — was 56.1% with everolimus and 45.1% with placebo.

Patients with hepatitis B virus, who made up 26.2% of the study sample, had the best prolonged overall survival with everolimus, but the reasons for this are not clear, Dr. Zhu explained.

"The results from EVOLVE-1 extend the list of failed phase 3 studies in advanced HCC, highlighting the challenge of developing effective therapies for this cancer," he said.

"I think the early phase 1/phase 2 data with everolimus in advanced HCC were perhaps somewhat weak, in the sense that we only performed a single-arm trial. We do not have a randomized trial to tell us the extent to which the efficacy observed was really due to the drug-induced benefit or just because of some selection bias in patients," he added.

The first-line use of the multikinase inhibitors sunitinib, brivanib, and linifanib in HCC has not shown efficacy. And no benefit was seen when erlotinib was added to sorafenib.

"The cancer is very heterogeneous, both clinically and biologically. As well, the underlying cirrhosis that exists in most patients with HCC adds to the complexity of treatment," Dr. Zhu said.

A Very Complex Cancer

The point about tumor heterogeneity was emphasized in a recent study (Gut. 2014;63:844-855).

In HCC, "not only might each patient have their own private cancer, but each tumor site may be genetically unique," Jordi Bruix, MD, from Hospital Clinic de Barcelona in Spain, told Medscape at the time.

Dr. Bruix explained that the molecular pathogenesis of HCC is extremely complex and heterogeneous. He noted that several trials have failed to improve the benefits of established therapies, but emphasized the need for more work.

"Studies assessing the sequential or combined application of those already known to be beneficial are needed," he said. "Also, new concepts are provided in regards to selecting and stratifying patients for second-line studies, which may help explain the failure of prior studies."

The study was sponsored by Novartis Pharmaceuticals, manufacturer of everolimus. Dr. Zhu reports financial relationships with sanofi-aventis, Exelixis, Eisai, and Daichi Sankyo.

JAMA. 2014;312:57-67. Abstract